Chronic endometritis - a constantly discussed issue in infertile women.

OBJECTIVE: A review of current knowledge on the pathophysiology, diagnostic and treatment options for chronic endometritis in infertile women. METHODS AND RESULTS: One of the major causes of failed in vitro fertilization (IVF) is undiagnosed intrauterine pathologies, including chronic inflammation of the uterine mucosa - chronic endometritis. However, some authors relativize the negative impact of chronic endometritis on reproductive outcomes. The etiopathogenesis of chronic endometritis is due to qualitative and quantitative changes in the endometrial microbiome with abnormal multiplication of microorganisms naturally occurring in the uterine cavity or vagina. There is no uniform consensus on the most common pathogen causing chronic endometritis. It is characterized by infiltration of plasma cells into the endometrial stroma outside the menstrual cycle, accompanied by hyperaemia and endometrial oedema. Clinical symptoms are very mild or absent. The diagnosis of chronic endometritis is often difficult because there is no specific clinical or laboratory diagnostic method. The following investigative options are commonly used for the diagnosis of chronic endometritis: diagnostic hysteroscopy, histopathological examination of the endometrium including CD 138 immunohistochemistry and culture from the uterine cavity. However, standardised international hysteroscopic and histopathological criteria for accurate diagnosis of chronic endometritis are still lacking. Empirically administered antibiotic therapy improves the success rate of pregnancy and delivery of a viable foetus in infertile patients with proven chronic endometritis. In addition to reviewing the current knowledge of chronic endometritis, this article discusses the importance of hysteroscopy in the diagnostic process. CONCLUSION: Chronic endometritis is often a clinically silent disease with negative impact on reproduction in infertile women. Although there are still many unresolved issues, the introduction of hysteroscopy into the diagnostic process is important for clinical practice; however, hysteroscopy even in combination with histological examination of the endometrium, often does not allow an unequivocal diagnosis of chronic endometritis. Further prospective randomised studies in a selected group of women with proven chronic endometritis and repeated failure to implant proven euploid embryos should refine this knowledge.

Solved problems of reproductive medicine in the Czech Republic 2020.

INTRODUCTION: During the 30th symposium of assisted reproduction held on November 11, 2020 in Brno, the solved problems in reproductive medicine in the Czech Republic in 2020 were presented. The selected topics have concerned not only current issues in the field of clinical embryology and genetics as well as gynecology, but also legislation and ethics. Discussed topics: 1. How much time does the doctor have in the CAR (centrum of assisted reproduction) outpatient clinic per patient and how does the embryologist communicate with clients? 2. Reproduction and PGT-M in oncology patients and patients at risk with hereditary oncogenic mutations. 3. Non-invasive genetic testing of embryos from culture medium. 4. Genome editing. 5. What is the need to monitor hormonal levels in stimulation protocols? 6. Monitoring and embryo selection for transfer/kryo. 7. Is it time to change the law on donor remuneration? METHODS: The topics were prepared in advance by authorized members of our company with the task of elaborating theses, which they presented in a separate conference block. The presentation and the discussion were broadcast directly from the broadcast studio at Hotel International via an online connection. After the conference, all discussion topics and comments were incorporated. CONCLUSION: The work presents the state of the solved problems of reproductive medicine in the Czech Republic.

Hysteroscopy in recurrent in-vitro fertilisation failure (TROPHY): a multicentre, randomised controlled trial.

BACKGROUND: The success rate of in-vitro fertilisation (IVF) remains low and many women undergo multiple treatment cycles. A previous meta-analysis suggested hysteroscopy could improve outcomes in women who have had recurrent implantation failure; however, studies were of poor quality and a definitive randomised trial was needed. In the TROPHY trial we aimed to assess whether hysteroscopy improves the livebirth rate following IVF treatment in women with recurrent failure of implantation. METHODS: We did a multicentre, randomised controlled trial in eight hospitals in the UK, Belgium, Italy, and the Czech Republic. We recruited women younger than 38 years who had normal ultrasound of the uterine cavity and history of two to four unsuccessful IVF cycles. We used an independent web-based trial management system to randomly assign (1:1) women to receive outpatient hysteroscopy (hysteroscopy group) or no hysteroscopy (control group) in the month before starting a treatment cycle of IVF (with or without intracytoplasmic sperm injection). A computer-based algorithm minimised for key prognostic variables: age, body-mass index, basal follicle-stimulating hormone concentration, and the number of previous failed IVF cycles. The order of group assignment was masked to the researchers at the time of recruitment and randomisation. Embryologists involved in the embryo transfer were masked to group allocation, but physicians doing the procedure knew of group assignment and had hysteroscopy findings accessible. Participants were not masked to their group assignment. The primary outcome was the livebirth rate (proportion of women who had a live baby beyond 24 weeks of gestation) in the intention-to-treat population. The trial was registered with the ISRCTN Registry, ISRCTN35859078. FINDINGS: Between Jan 1, 2010, and Dec 31, 2013, we randomly assigned 350 women to the hysteroscopy group and 352 women to the control group. 102 (29%) of women in the hysteroscopy group had a livebirth after IVF compared with 102 (29%) women in the control group (risk ratio 1·0, 95% CI 0·79-1·25; p=0·96). No hysteroscopy-related adverse events were reported. INTERPRETATION: Outpatient hysteroscopy before IVF in women with a normal ultrasound of the uterine cavity and a history of unsuccessful IVF treatment cycles does not improve the livebirth rate. Further research into the effectiveness of surgical correction of specific uterine cavity abnormalities before IVF is warranted. FUNDING: European Society of Human Reproduction and Embryology, European Society for Gynaecological Endoscopy.

Short follicular phase of stimulation following corifollitropin alfa or daily recombinant FSH treatment does not compromise clinical outcome: a retrospective analysis of the Engage trial.

To evaluate whether a short follicular phase of ovarian stimulation compromises the chance of pregnancy, subjects from a double-blind, randomized trial treated with a single dose of corifollitropin alfa (n=756) or daily recombinant FSH (n=750) were categorized as early responders if three follicles ≥17 mm were reached and human chorionic gonadotrophin (HCG) was administered prior to or on stimulation day 8, and as normal responders if three follicles ≥17 mm were reached and HCG was administered after stimulation day 8. In the corifollitropin alfa and recombinant FSH groups, 23.2% and 29.1%, respectively, were early responders (P=0.01). Regardless of the treatment group, the initial ovarian response was higher in early responders, but with two extra days of stimulation, the number and size of follicles on the day of HCG in the normal responders was similar to those of the early responders. The number of oocytes was similar in both response groups following corifollitropin alfa treatment (13.6 versus 14.5) and recombinant FSH treatment (12.8, both groups). The ongoing pregnancy rates were comparable for early and normal responders regardless of the treatment group, supporting successful outcome following a stimulation period of only 1 week.

The importance of advanced parental age in the origin of neurofibromatosis type 1.

Von Recklinghausen neurofibromatosis (NF1) is an autosomal dominant disorder with a prevalence about 1/3,000 (1/2,000-1/5,000 in various population-based studies). About 30-50% of cases are sporadic, resulting from a new mutation. NF1 is fully penetrant by mid-childhood, stigmata, and medical problems (neurological, dermatological, endocrine, ophthalmological, oncological) are highly variable. Advanced paternal age (APA) has been known to increase the risk of new germline mutations that contribute to the presence of a variety of genetic diseases in the human population. The trend in developed countries has been toward higher parental age due to various reasons. In a cross-sectional study, in two university hospital centers, data on parental age of 103 children (41 female) born between 1976 and 2005 with sporadic NF1 were analyzed. Parental age at birth was compared with the Czech general population matched to birth year. The mean NF1 sporadic case paternal age at birth was 32.0 years (95% CI 30.7-33.3 years) compared with 28.8 years (95% CI 28.6-29.1 years) in the general population (P < 0.001). The mean maternal age at birth was 27.4 years (95% CI 26.3-28.5 years) compared with 25.8 years (95% CI 25.5-26.0 years) in the general population (P < 0.05). The case-control difference in the father's age was higher than it was for the mother's age. Sporadic NF1 cases accounted for 35.6% of our entire NF1 cohort. We confirmed an association of advanced parental and particularly paternal age with the occurrence of sporadic NF1.

Comparison of different starting gonadotropin doses (50, 75 and 100 IU daily) for ovulation induction combined with intrauterine insemination.

PURPOSE: To prevent multiple pregnancies the goal of ovulation induction by gonadotropins is to achieve only mono-follicular development. The most important issue is therefore to determine the starting dose. The aim of this study is to compare three different starting doses of follitropin beta to assess the lowest effective dose. METHODS: We evaluated 92 cycles with ovarian stimulation for patients with unexplained infertility, anovulatory disorder or mild male factor. We prospectively divided patients into 50, 75 and 100 IU groups based on patients' response to clomiphene citrate treatment. RESULTS: We performed 87 intrauterine inseminations (95 % of cycles with ovulation induction). Five cycles were cancelled. We achieved 15 pregnancies; total pregnancy rate was 18 %. Pregnancy rate was 22, 10 and 28 % in 50, 75 and 100 IU follitropin beta groups. The average number of follicles was 2.0 ± 0.8, 2.2 ± 1.1 and 2.5 ± 1.8 (ns), total dose of gonadotropins (IU) 483 ± 192, 600 ± 151 and 830 ± 268 (p < 0.001), respectively. We observed one case of twins in 75 and 100 IU treatment group, as well (25 % risk). CONCLUSIONS: This study suggests that based on the dose which was chosen according to clomiphene citrate response, all treatment regimes were effective for ovulation induction. 50 IU of follitropin beta daily is the appropriate starting dose to support ovulation for clomiphene citrate-sensitive women. The disadvantage may be an increased risk of cycle cancellation due to low ovarian response. Daily doses 75 or 100 IU of rFSH increase total consumption of gonadotropins.

The Maribor consensus: report of an expert meeting on the development of performance indicators for clinical practice in ART.

STUDY QUESTION: Is it possible to define a set of performance indicators (PIs) for clinical work in ART, which can create competency profiles for clinicians and for specific clinical process steps? SUMMARY ANSWER: The current paper recommends six PIs to be used for monitoring clinical work in ovarian stimulation for ART, embryo transfer, and pregnancy achievement: cycle cancellation rate (before oocyte pick-up (OPU)) (%CCR), rate of cycles with moderate/severe ovarian hyperstimulation syndrome (OHSS) (%mosOHSS), the proportion of mature (MII) oocytes at ICSI (%MII), complication rate after OPU (%CoOPU), clinical pregnancy rate (%CPR), and multiple pregnancy rate (%MPR). WHAT IS KNOWN ALREADY: PIs are objective measures for evaluating critical healthcare domains. In 2017, ART laboratory key PIs (KPIs) were defined. STUDY DESIGN SIZE DURATION: A list of possible indicators was defined by a working group. The value and limitations of each indicator were confirmed through assessing published data and acceptability was evaluated through an online survey among members of ESHRE, mostly clinicians, of the special interest group Reproductive Endocrinology. PARTICIPANTS/MATERIALS SETTING METHODS: The online survey was open for 5 weeks and 222 replies were received. Statements (indicators, indicator definitions, or general statements) were considered accepted when ≥70% of the responders agreed (agreed or strongly agreed). There was only one round to seek levels of agreement between the stakeholders.Indicators that were accepted by the survey responders were included in the final list of indicators. Statements reaching less than 70% were not included in the final list but were discussed in the paper. MAIN RESULTS AND THE ROLE OF CHANCE: Cycle cancellation rate (before OPU) and the rate of cycles with moderate/severe OHSS, calculated on the number of started cycles, were defined as relevant PIs for monitoring ovarian stimulation. For monitoring ovarian response, trigger and OPU, the proportion of MII oocytes at ICSI and complication rate after OPU were listed as PIs: the latter PI was defined as the number of complications (any) that require an (additional) medical intervention or hospital admission (apart from OHSS) over the number of OPUs performed. Finally, clinical pregnancy rate and multiple pregnancy rate were considered relevant PIs for embryo transfer and pregnancy. The defined PIs should be calculated every 6 months or per 100 cycles, whichever comes first. Clinical pregnancy rate and multiple pregnancy rate should be monitored more frequently (every 3 months or per 50 cycles). Live birth rate (LBR) is a generally accepted and an important parameter for measuring ART success. However, LBR is affected by many factors, even apart from ART, and it cannot be adequately used to monitor clinical practice. In addition to monitoring performance in general, PIs are essential for managing the performance of staff over time, and more specifically the gap between expected performance and actual performance measured. Individual clinics should determine which indicators are key to the success in their organisation based on their patient population, protocols, and procedures, and as such, which are their KPIs. LIMITATIONS REASONS FOR CAUTION: The consensus values are based on data found in the literature and suggestions of experts. When calculated and compared to the competence/benchmark limits, prudent interpretation is necessary taking into account the specific clinical practice of each individual centre. WIDER IMPLICATIONS OF THE FINDINGS: The defined PIs complement the earlier defined indicators for the ART laboratory. Together, both sets of indicators aim to enhance the overall quality of the ART practice and are an essential part of the total quality management. PIs are important for education and can be applied during clinical subspecialty. STUDY FUNDING/COMPETING INTERESTS: This paper was developed and funded by ESHRE, covering expenses associated with meetings, literature searches, and dissemination. The writing group members did not receive payment.Dr G.G. reports personal fees from Merck, MSD, Ferring, Theramex, Finox, Gedeon-Richter, Abbott, Biosilu, ReprodWissen, Obseva, PregLem, and Guerbet, outside the submitted work. Dr A.D. reports personal fees from Cook, outside the submitted work; Dr S.A. reports starting a new employment in May 2020 at Vitrolife. Previously, she has been part of the Nordic Embryology Academic Team, with meetings were sponsored by Gedeon Richter. The other authors have no conflicts of interest to declare. DISCLAIMER: This document represents the views of ESHRE, which are the result of consensus between the relevant ESHRE stakeholders and where relevant based on the scientific evidence available at the time of preparation.The recommendations should be used for informational and educational purposes. They should not be interpreted as setting a standard of care, or be deemed inclusive of all proper methods of care nor exclusive of other methods of care reasonably directed to obtaining the same results. They do not replace the need for application of clinical judgment to each individual presentation, nor variations based on locality and facility type.Furthermore, ESHREs recommendations do not constitute or imply the endorsement, recommendation, or favouring of any of the included technologies by ESHRE.

The uterine length in women with Turner syndrome reflects the postmenarcheal daily estrogen dose.

AIM: To evaluate the effects of estrogen substitution on the uterine development in patients with Turner syndrome. METHOD: 57 women, aged 18.1-41.5 years, were treated with estrogen from puberty induction. RESULTS: In 21 women (37%), the uterus developed to >65 mm in length. The daily estrogen dose correlated with both uterine length (r = 0.29; p < 0.05) and Tanner breast stage (r = 0.44; p < 0.001). A negative correlation between age at artificial menarche and uterine length was found (r = -0.29; p < 0.05). The endometrium thickness was greater in women with an uterus length >65 mm (p < 0.05). In 50% of the women (18 were evaluated), an adult-shaped uterus developed. Previous growth hormone therapy (n = 32) had no impact on the uterus length. CONCLUSIONS: The uterine development was suboptimal in most patients. Further investigation is needed to optimize estrogen therapy for uterine development in patients with Turner syndrome.

High endometrial aromatase P450 mRNA expression is associated with poor IVF outcome.

BACKGROUND: The success of IVF treatment is dependent upon embryo quality and coordinated growth and differentiation of the endometrium. Aromatase P450 expression in the human endometrium is thought to be restricted to women with proliferative reproductive tract disorders such as endometriosis, leiomyomas and adenomyosis. METHODS: To determine whether endometrial aromatase P450 mRNA expression is prognostic of IVF outcome, we quantified transcript levels in biopsy specimens from a cohort of subfertile patients awaiting IVF treatment using real-time quantitative PCR. RESULTS: Aromatase P450 transcripts were detected in all endometria examined, although the levels varied considerably between samples, ranging from 0.22 to 486.6 arbitrary units (a.u.). The clinical pregnancy rate in women with high endometrial aromatase P450 mRNA levels (> or = 8.3 a.u.; n = 21) was 9.5% compared with 30.1% in those patients with low expression levels (<8.3 a.u.; n = 101) (P < 0.05). The cycle day of the endometrial biopsy, cause of infertility, age, parity, number of oocytes collected and number of embryos transferred did not differ between patients with high versus low endometrial aromatase P450 mRNA levels (P > 0.1). CONCLUSIONS: Our results indicate that endometrial P450 mRNA levels can identify women at increased risk of IVF treatment failure.